Alnylam Pharmaceuticals Inc

NASDAQ:ALNY

Earnings Call Transcript 2023-Q2

[Operator]

Good day and thank you for standing by. Welcome to the Alnylam Pharmaceuticals Q2 2023 Earnings Conference Call. At this time, participants are in a listen-only mode. After the speakers' presentation, there will be a question-and-answer session. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to hand the conference over to the company.

[Christine Lindenboom]

Good morning. I am Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam.

With me today on the phone are Yvonne Greenstreet, Chief Executive Officer; Tolga Tanguler, Chief Commercial Officer; Pushkal Garg, our Chief Medical Officer; and Jeff Poulton, Chief Financial Officer. For those of you participating via conference call, the accompanied slides can be accessed by going to the Events section of the Investors page of our website, investors.alnylam.com/events.

During today's call, as outlined on slide two, Yvonne will offer some introductory remarks and provide general context, Tolga will provide an update on our global commercial progress, Pushkal will review pipeline update and clinical progress, and Jeff will review our financials and guidance, followed by a summary of upcoming milestones before we open the call to your questions.

I’d like to remind you that today's call will contain remarks concerning Alnylam's future expectations, plans, and prospects, which constitute forward-looking statements for the purposes of the Safe Harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent periodic report on file with the SEC. In addition, any forward-looking statements represent our views only as to the date of this reporting and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements.

With that, I'd like to turn the call over to Yvonne. Yvonne?

[Yvonne Greenstreet, Chief Executive Officer]

Thanks Christine and thank you everyone for joining the call today. In the second quarter of 2023, we continue to make great progress across our business.

Starting with our commercial performance, the AMVUTTRA launch once again drove strong growth in our TTR franchise with 46% year-over-year growth and in total product sales with 43% year-over-year growth compared to the second quarter of 2022. We also delivered strong execution across our clinical pipeline, where notable results included positive 18 months data from our APOLLO-B Phase 3 study, reaffirming the potential of patisiran in ATTR amyloidosis of cardiomyopathy.

In July, we shared updated positive interim results from the Phase 1 study of ALN-APP in patients with early onset Alzheimer's disease, showing rapid and robust target engagement with sustained effect of six months with a single dose and an encouraging clinical safety and tolerability profile.

Additionally, our team executed on the business development side. Most notably, we entered into a strategic partnership with Roche for the development and commercialization of zilebesiran, providing us with what we believe is a remarkable opportunity to bring forward a potentially transformative program with a potential to disrupt the global treatment paradigm for hypertension.

We're also pleased to announce this morning that following our full cooperation with the government, the US Attorney's Office for the District of Massachusetts has now concluded and closed their case regarding the marketing and promotion of ONPATTRO in the US with no action. Operating with integrity has always been and will continue to be called to our Alnylam and we will continue to hold our business conduct, and in particular our interactions with healthcare providers and patients, the highest ethical standards.

As we move into the back half of 2023, we have several important catalysts, including the initial data from our KARDIA Phase 2 program zilebesiran, and pending a successful AdCom and positive regulatory review, the potential launch of ONPATTRO and ATTR amyloidosis with cardiomyopathy.

We believe all of this puts us on track with our Alnylam P5x25 goals, making Alnylam a top tier biotech company, developing and commercializing transformative medicines for rare diseases and beyond for patients around the world, driven by a high yielding pipeline of first and/or best-in-class product candidates from our organic product engine, all while delivering exceptional financial results.

Further, before I hand the call over, I'm very pleased to share that Akshay Vaishnaw Alnylam's President and Key Scientific Leader will be transitioning to a new and exciting role within the organization, serving as our first Chief Innovation officer. Akshay has been at the helm of driving science and innovation with Alnylam for nearly 18 years, and that effort has yielded an entirely new class of medicines. In his new role Akshay will become the company's key innovation leader, focused on the future of our R&D engine, which is the lifeblood of how we have and will continue to drive our research and development programs into transformative medicines as we continue to build a top tier biotech company.

With that, let me now turn the call over to Tolga for a review of our commercial performance. Tolga?

[Tolga Tanguler, Chief Commercial Officer]

Thanks Yvonne, and good morning everyone. Q2 was another strong quarter for Alnylam, driven by our TTR franchise and the strength of our ongoing launch of AMVUTTRA across several markets, which has started with the US where it has now been available for over a year. Our total net product revenues across all products grew 43% year-over-year in Q2.

Let me now review our TTR performance during Q2. The TTR franchise achieved $224 million in global net product revenues for ONPATTRO and AMVUTTRA, representing a 9% increase compared with the first quarter and 46% growth compared with the second quarter of 2022. At the end of the second quarter, over 3,490 patients were on ONPATTRO or AMVUTTRA treatment worldwide, up from over 3,160 patients at the end of the first quarter, representing 10% quarterly patient growth.

With respect to our international performance, total TTR second quarter product sales increased 6% versus the first quarter, driven by strong AMVUTTRA demand in Japan and the UK, UK being our most recent launch market. After more than six months since its launch, the AMVUTTRA demand growth in Japan is particularly encouraging with new patient growth being driven by a mix of switches from tafamidis, as well as patients naive to therapy.

Importantly, ONPATTRO continue to deliver steady growth in markets where AMVUTTRA is not yet available, a sign of our robust demand generation activities as we position these markets for upcoming AMVUTTRA launches.

Now let me turn to the US where combined sales of ONPATTRO and AMVUTTRA increased by 12% versus the first quarter and a robust 72% year-over-year growth, representing the fourth consecutive quarter of achieving TTR growth in excess of 70% on a year-over-year basis in the US, since the launch of AMVUTTRA in the third quarter of 2022. This significant growth was primarily driven by a 15% increase in demand, which more than offset the decrease in patients on ONPATTRO that switched to AMVUTTRA and the robust demand was slightly offset by inventory dynamics, which decreased reported growth by approximately 2%, with channel inventory reductions to both products.

AMVUTTRA continues to expand the overall TTR polyneuropathy franchise as reflected by our year-over-year growth. The steady growth of AMVUTTRA performance in the US is a testament to the significant unmet need of patients with TTR polyneuropathy, our commercial capabilities and naturally the product profile of AMVUTTRA.

Our leading performance indicators also continue to trend favorably, including the expansion of our prescriber base and favorable access, resulting in patient compliance rates of over 90%. A year into launch, we have increased our prescriber base by almost 50% through a balanced mix of academic centers and community-based specialists, while switching a majority of the patients who are ONPATTRO at the time of AMVUTTRA launch.

Now update on our Ultra-Rare franchise. We are proud to have developed and commercialized two Ultra-Rare products, transforming small patient populations that suffer greatly. GIVLAARI and OXLUMO together delivered $82 million in combined product sales during the second quarter, representing a 14% increase compared with the first quarter and a solid 37% growth compared with the second quarter of 2022.

We ended the quarter with more than 570 patients on GIVLAARI commercial therapy and more than 350 patients on OXLUMO commercial therapy, representing 8% combined quarterly growth in patients on our Ultra-Rare products compared with the first quarter of 2023.

For GIVLAARI, global revenue growth of 21% in Q2 compared the first quarter was driven by the following. In the US, we had an increase in the number of patients on therapy and an increase in patient compliance rates. A robust 29% in our international markets, which was impacted positively both by demand growth as well as order timing in our partner markets.

For OXLUMO, flat quarterly revenue was a result of fewer US patients on a loading dose regimen, which offset modest patient growth. Growth in international markets was primarily driven by order timing in partner markets, which was partially offset by an unfavorable pricing mix in our European markets. Overall, Q2, 2023 was another quarter of healthy growth in revenues in our quest to serve more patients.

With our -- with over a year since launch, we are particularly pleased with the steady growth of AMVUTTRA, which represents an important therapy option for hATTR amyloidosis patients with polyneuropathy.

With that, I will now turn it over to Pushkal to review our recent R&D and pipeline progress. Pushkal?

[Pushkal Garg]

Thanks Tolga, and good morning, everyone. Let me start by updating you on our TTR franchise where as you know, we're conducting two large studies, APOLLO-B and HELIOS-B to evaluate the efficacy and safety of patisiran and vutrisiran, respectively in ATTR cardiomyopathy.

The sNDA for patisiran is under FDA review based on the positive results of the APOLLO-B study, and as we recently announced, the application will be discussed at the Cardiovascular and Renal Drugs Advisory Committee on September 13th.

We also announced today that enrollment in a US expanded access protocol for patisiran that was open shortly after the APOLLO-B readout last August has completed. The EAP was established to provide access to patisiran for patients with ATTR amyloidosis with cardiomyopathy who've had an inadequate response to or cannot tolerate currently available treatment. The EAP was offered at 20 centers in the United States and the pre-specified enrollment target of 200 patients was met in about 10 months, indicating significant demand for this potential therapy.

Another important recent update on patisiran was the presentation of 18-month results from APOLLO-B at the recent ESC Heart Failure Meeting. As a reminder, after the 12-month double-blind period of the study, all patients were eligible to receive patisiran during the open-label extension period of the trial. In the new analysis, we were very encouraged to see that favorable effects on functional capacity as assessed by the six-minute walk test, as well as on health status and quality of life as assessed by the Kansas City Cardiomyopathy Questionnaire were sustained in patients receiving patisiran through 18 months. According to both of these endpoints, patisiran appeared to slow the decline in functional ability and health status that is typical for this disease.

And similarly in patients who receive placebo during the double-blind period, initiation of patisiran in the OLE period was associated with initial evidence of stabilization, both six-minute block test and KCCQ relative to the double-blind period. Importantly, patisiran continued to demonstrate an encouraging safety profile through 18 months of treatment with no new safety concerns identified.

We saw encouraging evidence of efficacy with other secondary and exploratory endpoints as well. Continued treatment with patisiran through 18 months was associated with relative stability in both NT-proBNP, a measure of cardiac stress and Troponin I, a measure of cardiac injury. And patients who rolled over from placebo to active treatment during the OLE saw slowing in relative stabilization of the rapid increases that were seen during the double-blind period.

In addition, while the APOLLO-B study was not designed to show benefits on outcomes of hospitalizations or death, we were encouraged to see non-significant trends favoring patisiran treatment in these outcome endpoints, with extended follow-up during the OLE period.

As we previously announced, we've submitted the 18 months results to the FDA as an amendment to our sNDA for patisiran, we look forward to continuing our engagement with the agency, including at the upcoming advisory committee and if patisiran is approved, expanding its label to bring patisiran to patients with ATTR amyloidosis with cardiomyopathy.

We were also very excited to share initial human proof-of-concept data on ALN-APP, our first RNAi therapeutic designed for CNS delivery, which is in development for the treatment of Alzheimer's disease and cerebral amyloid angiopathy. At the AAIC Congress in July, we presented updated positive interim results from the Phase 1 study in patients with Early-Onset Alzheimer's disease. At the time of this interim look, 20 patients had been enrolled in three single dose cohorts in Part A of the ongoing Phase 1 study.

To date, we've studied three dose levels, 25, 50, and 75 milligrams with four to six patients dosed in each cohort. Excitingly, ALN-APP treatment resulted in rapid dose dependent and sustained reductions of both soluble APP alpha and beta, biomarkers of target engagement in the CSF. We saw rapid knockdown as early as day 15 and observed maximum knockdown of 84%, 90% respectively for soluble APP alpha and beta. And at the highest dose tested 75 milligrams, the median knockdown was greater than 55% for both biomarkers and sustained for at least six months.

The safety of single doses of ALN-APP has been encouraging as well. All adverse events were mild or moderate in severity, and CSF parameters have not revealed any significant abnormalities to date.

Further exploration of single doses of ALN-APP is ongoing in Part A. In addition, Part B, the multiple dose part of the study has been initiated in Canada where the majority of the Part A clinical trial patients were enrolled. The multiple dose part of the study remains on partial clinical hold in the United States due to findings observed in prior non-clinical chronic toxicology studies. In some, I'm thrilled about these impressive human data that provide the first ever evidence that we may be able to use RNAi to sign up disease causing transcripts from the CNS and look forward to providing additional program updates in the future.

Let me now turn to recent progress with zilebesiran in development for the treatment of hypertension. We're very excited to recently announce the Phase 1 data were published in the New England Journal of Medicine, highlighting the medical importance of the substantial and durable lowering of blood pressure seen with single doses of zilebesiran. This now marks Alnylam's 11th publication in this prestigious medical journal.

Yvonne has already highlighted the exciting collaboration with Roche we recently announced for the development commercialization of zilebesiran on the basis of these impressive Phase 1 data. We're now looking forward to results of the KARDIA-1 dose ranging study, which is on track for top line data in Q3. In addition, we're also pleased to have recently completed enrollment in the KARDIA Phase 2 -- KARDIA-2 Phase 2 study, which aims to evaluate the safety and efficacy of zilebesiran in patients with uncontrolled hypertension when added on top of other anti-hypertensive medications. We expect to report top line results from this study in early 2024.

These are just a few highlights from our broad and innovative pipeline driven by our underlying organic product engine that we expect will deliver sustainable growth for Alnylam in the years to come.

With that, let me now turn it over to Jeff to review our financial results in upcoming milestones. Jeff?

[Jeff Poulton, Chief Financial Officer]

Thanks Pushkal, and good morning everyone. I'm pleased to be presenting a summary of Alnylam's Q2 2023 financial results and discussing our full year guidance.

Starting with the summary of our P&L results for the second quarter. Total product revenues for the quarter were $306 million or 43% growth versus Q2 2022. Tolga previously indicated the increase is primarily related to growth in TTR product revenues driven by the launch of AMVUTTRA in the US in the third quarter of 2022, as well as increased patients on GIVLAARI and OXLUMO therapies. The impact of foreign exchange rates on our product sales has moderated on a year-over-year basis with constant exchange rate growth now only 1% higher than our reported 43% year-over-year growth.

Net revenues from collaborations for the quarter were $6 million or 35% decrease compared with the second quarter of 2022, primarily due to operating variability, including the level of work reimbursed in our collaboration with Regeneron.

Royalty revenue during the quarter was $7 million, which was driven by Novartis's sales of Leqvio, which launched in the US in the first quarter of 2022. Despite the modest growth for revenues from collaborations and royalties, we remain confident in achieving a full year result with our $100 million to $175 million guidance range, primarily driven by our Regeneron collaboration and Leqvio royalties and milestones.

Gross margin on product sales was 75% in the quarter, representing a 9% decrease compared with the second quarter of 2022. The decrease was primarily due to fees incurred associated with canceling manufacturing commitments for ONPATTRO and other adjustments to inventory as demand for ONPATTRO continues to decrease driven by ongoing patients switching to AMVUTTRA.

Our non-GAAP R&D expenses increased 11% in the second quarter compared to the same period in 2022, primarily due to increases in headcount to support our R&D pipeline and development expenses associated with the KARDIA-1, KARDIA-2 Phase 2 clinical studies.

Our non-GAAP SG&A expenses increased 14% in the second quarter compared to the same period in 2022, primarily due to increased headcount and other investments supporting our strategic growth including the global launch of AMVUTTRA.

Our non-GAAP operating loss for the quarter was $154 million, representing a $7 million improvement compared with Q2 2022, driven by strong top line growth offset by more moderate growth and operating expenses.

Finally, we ended the quarter with cash, cash equivalents and marketable securities of $2.1 billion compared to $2.2 billion at the end of 2022, with a decrease primarily due to our operating loss year to date. We continue to believe our current cash balance is sufficient to bridge us to a self-sustainable financial profile.

Now I'd like to turn to our full year 2023 financial guidance where we are reiterating our previously issued guidance. Starting with net product revenues, we continue to anticipate combined net product revenues for our four commercialized products will be between $1.2 billion and $1.285 billion. Our guidance for net revenue from collaborations and royalties remains a range between $100 million and $175 million. And our guidance for combined non-GAAP R&D and SG&A expenses remains unchanged and has arranged between $1.575 billion and $1.65 billion.

Let me now turn from financials and discuss some key goals and upcoming milestones slated for mid and late 2023. We will, of course, be executing on global commercialization of our four commercial products.

With patisiran, we look forward to the upcoming meeting of the Cardiovascular and Renal Drugs Advisory Committee on September 13th with the PDUFA date shortly thereafter on October 8th. Later this quarter, we expect to report top line results from the KARDIA-1 Phase 2 study of zilebesiran. We also intend to report top line results from Phase 1 studies of ALN-TTRsc04, and development for the treatment of ATTR amyloidosis and ALN-KHK and development for the treatment of type two diabetes.

Our partnered programs Sanofi expects to report additional results from the Phase 3 ATLAS program with patisiran, an investigational RNAi therapeutic and development for the treatment of hemophilia A or B with or without inhibitors. Additionally, Vir expects to report further results from Phase 2 combination trials of ALN-HBV02, and development for the treatment of chronic HPV infection.

Let me now turn it back to Christine to coordinate our Q&A session. Christine?

[Christine Lindenboom]

Thank you, Jeff. Operator, we'll now open the call for questions. To those dialed in, we would like to ask you to limit yourself to one question and then get back in the queue if you have additional questions.

[Operator]

Thank you. We'll now conduct the question-and-answer session. [Operator Instructions]

Our first question comes from Mike Ulz of Morgan Stanley. Your line is now open.

[Michael Ulz, Morgan Stanley]

Hey, guys. Thanks for taking the question. Maybe just quickly, any updated thoughts on the upcoming AdCom ONPATTRO and ATTR CM in terms of why the FDA decided to host the panel and then where you expect the focus to be? Thanks.

[Yvonne Greenstreet, Chief Executive Officer]

So, thank you for that question. Clearly, we're actively preparing for the advisory committee. We're really looking forward to presenting the data that we have from APOLLO-B. Whilst there are no specific questions at this time, we believe that the topics are going to be focused on the clinical meaningfulness of changes in the six-minute walk test and the KCCQ, particularly given the fairly recent FDA guidance around the utility of these endpoints and in patients with heart failure.

We really believe that we have compelling data for APOLLO-B study across a wide range of endpoints and supported by additional validation from the recent 18-month data that has Pushkal described. We have submitted to the FDA.

Pushkal, anything else to add?

[Pushkal Garg]

I think you've really covered it, Yvonne. I think, it really is -- we're -- our preparations underway. We feel really good about the data set that's been generated with APOLLO-B, and what we're seeing is evidence of stabilization across a series of endpoints, which is really critically important. Patients with this disease really value their functional ability and their quality of life. And what we're seeing across multiple measures is that patisiran appears to enable that, and that's reconfirmed with the extended OE data that we submitted. And we look forward to presenting that to the advisory committee as they -- to their review.

[Yvonne Greenstreet, Chief Executive Officer]

Thanks Pushkal. Next question?

[Operator]

One moment for the next question. Our next question comes from Luca Issi of RBC. Your line is now open.

[Unidentified Analyst]

Great. Thanks for taking our questions. This is Lisa on for Luca. I just wanted to dive into some specifics on the Roche deal first, zilebesiran. We know the deal entails $310 million upfront, plus substantial near term milestones. Your partner Roche has said that they expect to invest another $275 million to get to the end of Phase 2. So, just wondering if you can add any clarity on the $275 million and if this is part of the substantial near term milestones that you're expecting. Thanks.

[Yvonne Greenstreet, Chief Executive Officer]

That's a great question, and a good opportunity for clarification. I'll pass it on to Jeff in a moment, but I just wanted to remind everybody that really what we feel that we have here in our hands with zilebesiran is a game changing therapy for patients with hypertension, really to maximize the value and drive a successful global product launch.

We want to come to the market with cardiovascular outcomes data to help inform the various stakeholders. And obviously, that's a significant endeavor. And the collaboration with Roche allows us to bring together our leadership and RNAi is what is their proven global commercial footprint and capabilities and help us maximize the resources and capabilities in order to be successful here. But I think it's important to be specific about the -- about some of the details of the milestones. So Jeff, maybe you could…

[Jeff Poulton, Chief Financial Officer]

Yeah. Let me just clarify that. So, the substantial near term development milestones that we had referenced when we announced the deal are, there's actually $365 million in potential development milestones that we could earn, and that's broken down as $65 million for the initiation of KARDIA-3, which is the additional Phase 2 study that Pushkal talked about on the deal call. And we expect that study to initiate next year. And then an additional $300 million for the first patient in on the CPOT [ph], the Phase 3 study. So taken together, that's the $365 million.

When you look at that in combination with the development cost sharing, where Roche will put 60% of the bill and Alnylam will put 40% of the bill, really, from an out-of-pocket perspective for Alnylam to take this drug forward to the market really minimizes the financial burden for us, which allows us to then reallocate capital across our pipeline and hopefully drive additional growth.

[Yvonne Greenstreet, Chief Executive Officer]

That's great, Jeff. Thank you. Next question?

[Operator]

One moment for our next question. Our next question comes from Citi with David Lebowitz. Your line is now open.

[David Lebowitz, Citi]

Thank you very much for taking my question. A question on the submission of the 18 months data for ONPATTRO, inclusion. I know the PDUFA date stands in October. Is there any consideration by the FDA consider this a major amendment and move the PDUFA date three months down the road? Or have they not exhibited any such intent at this point?

And on franchise growth, while there's no question the overall franchise is growing quite well, how is ONPATTRO maintaining as much share as it is to this point, given how well AMVUTTRA is doing?

[Yvonne Greenstreet, Chief Executive Officer]

Yeah. Two great questions. So, I'll take the question on the PDUFA data and then I'll hand over to Tolga to speak to your overall franchise question around using the dynamics between ONPATTRO and AMVUTTRA. We're continuing to anticipate a PDUFA date of October, the eighth, and we're working towards that. If that changes, of course, we'll communicate any new information. But as of this moment, we are continuing to expect the PDUFA date of October, the eighth.

Tolga, do you want to turn to the question on ONPATTRO dynamics?

[Tolga Tanguler, Chief Commercial Officer]

Sure. Happy to. So, the way I think we should think about this is US and are newly recently AMVUTTRA launch markets and those markets that are continuing to have only ONPATTRO as an option in within the franchise.

As I indicated on the call, uh, if you look at our US growth in the TTR categories, 70% quarter-over-quarter growth would last four consecutive quarters, which is quite substantial. And that's really primarily driven by AMVUTTRA. In fact, the number of ONPATTRO patients that remains in the US at the time when we launched AMVUTTRA is getting smaller and smaller. So we're very pleased with how patients are switching over to AMVUTTRA.

And we've also seen in other markets like Japan, now we're start seeing in France with very creative AP2 program name patient program as was in the UK. We're getting accelerated approvals in those several key markets to make sure that we're providing AMVUTTRA is an option. Now, the reason why you see a good persistent growth on ONPATTRO and albeit a smaller portion of our business is because markets like Italy and Spain where AMVUTTRA is still not yet available, we're seeing a good robust growth. And that's, again, a testament to the need of an option in this market in polyneuropathy, as well as our commercial abilities that we've been able to drive good, strong, robust growth, which obviously positions us very nicely at the time of AMVUTTRA launch in these other markets. We're going to start seeing -- we'd like to see a good strong uptake of AMVUTTRA and subsequent switches from ONPATTRO to AMVUTTRA.

[David Lebowitz, Citi]

Thanks for taking the question.

[Yvonne Greenstreet, Chief Executive Officer]

Yeah, thanks. Thanks. Thanks Dave. Let's turn to the next question.

[Operator]

One moment for the next question. Our next question comes from Paul Matteis of Stifel. Your line is now open.

[Paul Matteis, Stifel]

Hey, thanks so much. I wanted to ask about the timing and any reason behind Akshay's role change. I think Akshay became President just 18 months ago. And it's such a pivotal time for Alnylam with the AdCom coming up, the HELIOS-B data. I haven't heard him at all on this call. So, I was just curious if you could expound upon this a little bit, and clarify if there's anything else behind the decision or this announcement today. Thanks so much.

[Yvonne Greenstreet, Chief Executive Officer]

So, thank you for that question. Look, I'm personally delighted that Akshay is going to take on this opportunity to become our first Chief Innovation Officer and that capacity continue to focus on helping to deliver continued success with respect to our R&D organization. We're also delighted that we've built a really strong, robust capability across the research and development organization. And that's allowed Akshay to be able to focus more specifically on innovation as we build a top tier biotech company.

So, I think this is a terrific step forward for the company. There's no specific reason for this timing other than the fact that actually felt that that we're now in a position where we have a really strong capability, which allows him to take on a much more focused role for the company and he'll continue to be involved in all the important upcoming catalysts and milestones that you've just described. He's not on the call today because he's actually on vacation, but I'm sure we will -- we may well hear him on a upcoming call in the future. So, thanks for that question, Paul.

[Paul Matteis, Stifel]

Okay. Thank you.

[Operator]

One moment for our next question. Our next question comes from Ritu Baral of TD Cowen. Your line is now open.

[Ritu Baral, TD Cowen]

Good morning, guys. Thanks for taking the question, Yvonne and Pushkal, I wanted to dig down a little bit more on the preparation into the advisory committee, whether it's yours or ours or FDA's. Right now, are you planning to be able to discuss any additional data cuts later than 18 months from APOLLO-B or any data out of that fully enrolled expanded access plan? And is -- do you believe that there's any shift in understanding around these endpoints, given the recent BridgeBio data and how all of these endpoints and other endpoints like outcomes sort of link together?

[Yvonne Greenstreet, Chief Executive Officer]

Thanks Ritu. There are kind of few questions there and we sort of -- maybe sort of unpick them. So, in terms of our AdCom preparations, any additional data that we're providing the FDA beyond the 18-month data that we've already referenced. And then secondly, kind of is any shifts in understanding with respect to the endpoint selection.

So, I mean, Pushkal, maybe you could those two questions.

[Pushkal Garg]

Yeah. Absolutely. Thanks Ritu. Look, in terms of the AdCom preparations, we're again entering into the period where we're trying to -- we're really pulling together aspects of our preparation. We feel very good about how the team is prepared for this. And it's all based on incredibly strong data coming out of APOLLO-B and reaffirmed by the OEL data that we talked about early -- and earlier. And really it's the fact that across multiple measures, within the study, looking at endpoints like functional ability and quality of life, the biomarker data that are predictive of longer term outcomes, we're seeing evidence of relative stability. Patients who get on this drug appear to have less progressive decline.

And we shared data last year at R&D Day showing favorable impacts on progression on NYHA Class and ATTR disease stage. So, all of this really paint a picture of delayed progression when patients are put on a silencer with this disease. And that's really important. We keep hearing from clinicians in the field that that's really important to patients. These are patients in their seventies and eighties. They value their functional ability and their quality of life. And so, these changes are meaningful to them. And I think what I can say is that the AdCom will be pulling together those various arguments. We've received a lot of support both from the data side, but also from external key opinion leaders, et cetera. And so, we'll look forward to making those points at the advisory committee and interacting with the agency and the panel there.

Vis-a-vis BridgeBio, look, I think what I would say is, first of all, it's great news for patients. It looks like there may be potentially an additional medicine as we kind of learn more about this data and an additional stabilizer for patients with this disease. And I think it hats off to the patients, the investigators, and the colleagues at BridgeBio because it was -- it's been a challenging time and it's great to see that they've pulled out what looks to be a very positive study in that regard.

I think as it relates to our franchise, we really remain excited about what the silencer profile looks to be. Again, building on what I just said about APOLLO-B emerging data that we're seeing, again, not statistically significant, but emerging trends with regard to outcomes coming out of APOLLO-B both on mortality and hospitalization.

And I think the key, we'll be looking for more data at the ESC meeting. But I think what the results highlight is that in -- while we are diagnosing patients earlier with this disease, and that's been a big question in the field, these patients still endure ongoing progression. So that in APOLLO-B looks like that's reaffirmed in the BridgeBio data and an effective therapy can show a benefit to that population. And I think that reaffirms the design elements of HELIOS-B. So we're very excited about that as well.

[Ritu Baral, TD Cowen]

Great. Thanks.

[Operator]

One moment for our next question. Our next question is coming from Salveen Richter of Goldman Sachs. Your line is now open.

[Unidentified Analyst]

Thanks for taking our question. This is Tommy on for Salveen and congrats on all the progress. Our question is also on BridgeBio and HELIOS-B. So, we saw from BridgeBio that there is this imbalance in TAF drop-in rates between the two arms that have this impact on separation. How are you thinking about the risk there to HELIOS-B given the drop in allowance? And kind of on the other hand, would HELIOS-B be able to give physicians insight into potential additive benefit when you combine Alnylam insurance stabilizer? Thank you.

[Yvonne Greenstreet, Chief Executive Officer]

Okay. So, two questions there for you, but maybe I'll just start off by saying that we're actually really pleased to see the BridgeBio results because it really kind of reaffirms that even if patients were diagnosed earlier in the disease, they continue to have disease progression where an effective therapy, is able to demonstrate benefits in these earlier stage patients. So, I think, we're actually really kind of pleased that this gives us increased confidence actually in delivering a successful HELIOS-B.

But Pushkal, maybe you can talk specifically about the TAF imbalance in -- TAF drop-in rates, potential impact on HELIOS-B and also, thinking about combination approaches stabilizes and silences.

[Pushkal Garg]

Yeah. Look, I think, as it relates to TAF drop-in rate, I think as we've talked about in the past, we've got careful measures in place and the way that the study was designed, and we feel good about the drop-in rate, that's there. It's substantially below our internal assumptions as we design the study. We're not going to provide any more specific updates on that, but we're very encouraged by what we're seeing with regard to that and about the overall design of the study.

The study allows for a proportion of patients to be on background tafamidis, entering into the study just like we did in the APOLLO-B study. As we've said our targets were around 50%, but we've operationally come in below that. And so, I think we will get interesting data emerging from that study in terms of how the drug functions as a monotherapy, but as well as on top of background tafamidis.

[Yvonne Greenstreet, Chief Executive Officer]

Thanks. Next question please.

[Operator]

One moment for our next question. Our next question comes from Maury Raycroft of Jefferies. Your line is now open.

[Yvonne Greenstreet, Chief Executive Officer]

Hi, Maury.

[Maury Raycroft, Jefferies]

Hi, thanks for taking my question. For the 200-patient expanded access program study, can you talk about the types of patients you've enrolled timeline to data, and how the data will be leveraged as it relates to regulatory or commercial plans?

[Yvonne Greenstreet, Chief Executive Officer]

Yeah. Pushkal, that's a question for you around the EAP types of patients and then also thinking about how these data may be used going forward.

[Pushkal Garg]

Yeah. Maury, thanks. When the APOLLO-B data came out, it posed -- it brought forward the potential for an alternative mechanism for patients with this disease. As we've talked about multiple times during the call, these patients despite available standard-of-care therapy with tafamidis, continue to progress. And so what we did was establish an expanded access program, that at 20 US centers that enabled patients who were experiencing progression or were otherwise intolerant of available therapy to avail themselves with patisiran with their physician support. So that was open at 20 centers.

And as I mentioned, that enrolled actually relatively rapidly, we had 200 patients. It was actually on the order of about three patients every two days that was enrolled -- two patients every three days -- sorry, that was enrolled in this EAP program. And it really highlights, I think, what we've been saying and what we've been hearing a lot from the clinical community and the patient communities that patients continue to progress with this disease and they need additional therapies. And so, I think that's important as we think about bringing forward patisiran in this disease. And then, hopefully patisiran as well based on the results of HELIOS-B.

[Yvonne Greenstreet, Chief Executive Officer]

Yeah. Thanks Pushkal. I think the point about continued unmet medical need is really the important one here. See the patients who are continuing to progress and patients that need alternative therapeutic approaches. Next question, please.

[Operator]

One moment for our next question. Our next question comes from Eliana Merle of UBS. Your line is now open.

[Eliana Merle, UBS]

Hey, guys. Thanks so much for taking the question. For HELIOS-B, can you elaborate on your rationale for using Andersen-Gill as a statistical method versus the Finkelstein–Schoenfeld pairwise analysis that was used in the stabilizing Phase 3, such as the recent BridgeBio data?

And then second, just in terms of the event rate, how are you thinking about the proportion of cardiovascular hospitalizations that will come from the urgent heart failure visit component and the importance of including the urgent heart failure visit as part of this endpoint definition? Thanks.

[Yvonne Greenstreet, Chief Executive Officer]

Pushkal, there's maybe two questions for you.

[Pushkal Garg]

Sure. So, Ellie, I think there's a multitude of approaches to conducting survival analysis and outcome analysis that take advantage of the fact that you're looking at recurrent events and events over time. And our statisticians obviously spend a lot of time thinking about what's the optimal way to demonstrate the clinical benefit. And that's highlighted in a statistical analysis plan that's aligned with the agency.

In this instance, one of the reasons for preferring the Andersen-Gill is the fact that there we allow for variable follow up in the context of the outcomes analysis. And the Andersen-Gill really allows us to fully leverage that, whereas other approaches would allow us to use a fixed time of follow-up, and frankly the shortest amount of follow up. So, we think it gives us a little bit of an analytic or power advantage to do it that way.

With regard to the various components of the endpoint, I think what's really important, Ellie, is maybe just a larger picture. We're trying to capture clinically relevant events that connote to heart failure worsening, and the need for care in patients with this disease. And so that's why care is increasingly provided in different geographies, in different places, including in hospitals and urgent care centers, et cetera. And so, we look at the totality of all of that as indicating clinically relevant heart failure events that we may have an opportunity to affect with an effective therapy. And that's why that we've kind of captured that aspect in the endpoint structure.

[Eliana Merle, UBS]

Great. Thanks so much.

[Operator]

One moment for our next question. Our next question comes from William Pickering of Bernstein. Your line is now open.

[William Pickering, Bernstein]

Good morning. Thanks for taking my question. I was wondering what percent of AMVUTTRA patients are getting dosed at home so far. And yeah, as you look ahead to future competitive dynamics versus vutrisiran [ph], what does your market research tell you about how patients are thinking about the trade-offs between physician delivered therapy quarterly versus monthly self-injection? Thank you.

[Yvonne Greenstreet, Chief Executive Officer]

Tolga, there's two questions for you. The first relating to home infusion and the second I think relating to vutrisiran, how we're thinking about differentiation.

[Tolga Tanguler, Chief Commercial Officer]

Yeah. No, thank you. Great question. Look, I think, the way we should be thinking about this is AMVUTTRA will be the only disease reversing treatment for polyneuropathy dose four times a year. And not only, I think this really positions the product well from a convenience perspective, but there are number of important features that we believe will make AMVUTTRA incredibly competitive. Having a unique MOA, erupted and sustained disease reversal, obviously with a few dose, and we should also remember, we have five years of experience now in this category, and now one full year in the US, promoting AMVUTTRA that we really have been able to establish numbering of important patient and physician capabilities, starting from the fact that, this is a Part B product and where we have excellent coverage of reimbursement benefits and then going into the patients, whether it's site of care and providing various options, not just in the home, but also in other different sites of care, whether it's an infusion center or in a hospital care. And more importantly than supporting the patient benefit.

So, one of the question that you ask is since we've launched ONPATTRO and now AMVUTTRA, we have over -- nearly a third of our patients are getting home care. And what's really also important is to remember that, almost all of our patients over 90% stays on therapy. Not only get a good convenience access to these medicines, but also has the ability to stay on therapy. We have a very, very minimal dropouts. So, with all these other features that we offer, we believe this is going to remain a very significant benefit.

And another important one is obviously to remember, unlike Part D until 2025, our patients, nearly 70% of them has zero copay. And this will continue to be an important benefit. So, we are very -- we feel very good about how AMVUTTRA is already being positioned in the market, first with the values that we bring on the table, as well as some of the services that we've set out there for the last five years.

[William Pickering, Bernstein]

Very helpful. Thank you so much.

[Operator]

One moment for our next question. Our next question comes from Genie Wang of Barclays. Your line is now open.

[Gena Wang, Barclays]

Thank you for taking my questions. I also have one question regarding HELIOS-B. I think, Pushkal, in the past, you comment on [indiscernible] dropping rate, I think early on was in the low single digit. I don't -- I'm pretty sure now increase. But do you think, so far, say if we're using a TRIBUTE [ph] study as a benchmark where your dropping rate, it will be much lower than that. It's doing say, below 10%. And also do you see blinded events and how's that event's tracking versus your initial assumption?

[Pushkal Garg]

Yeah. Thanks Gena for your questions. Look, I think in terms of the drop-in rates, as you can imagine, is over the course of a three-year plus study, you're going to see those rates are going to evolve over time. What I can say is that the rates are -- the drop-in rates are significantly below our planning assumptions. And so, we feel very good about the overall powering of the study. There's a multitude of factors that contribute to how a study is powered, et cetera, and how that's going to turn out. And again, when we look at all of those elements, we feel good about the study.

In terms of event rates, of course, we have a cracker jack clinical and statistical team, they're responsible for monitoring a study, and ensuring the quality of the data that come in and the integrity of the study. And we feel, again, really positive about what we're seeing overall. And we have a long history of people in that -- in those teams who've designed and executed really successfully team -- studies in this field, including APOLLO-B, and so again, we feel very good about what we're doing here with HELIOS-B.

[Yvonne Greenstreet, Chief Executive Officer]

Thanks for the question, Gena.

[Operator]

One moment for our next question. Our next question comes from Leland Gershell of Oppenheimer. Your line is now open.

[Leland Gershell, Oppenheimer]

Hey, thanks for taking the question. Just a question from me, as we look forward to the ALN-KHK data, obviously it's being looked at in type two diabetes and you'll be looking at glycemic indices. So, we'll see presumably data there. But just wondering, where that target sits could be useful for other related conditions. Weight loss, obesity, essentially NASH. Just wondering what your thoughts may be with respect to taking that, that candidate in one of those directions. As you will be looking at overweight, obese patients in the study, and even though you may have two other programs in NASH, those are both partnered. Wondering if you have freedom to pursue NASH if you'd like for KHK. Thank you.

[Yvonne Greenstreet, Chief Executive Officer]

Yeah. That's a great question. And just remind everybody that KHK is a genetically validated target involves the metabolism of [indiscernible] and that's relevant to the development of diabetes. And as you point out, obesity as well. And clearly we're focused in our Phase 1 study addressing, target engagement and safety, and also looking at a range of relevant biomarkers with respect to glucose metabolism and insulin levels.

But I think you raised an interesting question, which is that broad potential of KHK and metabolism in general. Pushkal, maybe you want to provide some perspective?

[Pushkal Garg]

Yeah. Leland, I think it's a really insightful question in the sense that this -- we've seen epidemiologically that with rise in fructose consumption, we've seen parallel increases both in diabetes, overweight, NASH, and a number of metabolic syndrome type diseases that all travel together. And it's entirely possible that by perturbing this pathway with a RNAi mechanism, that we actually may have beneficial effects in a number of these different domains.

So, what's exciting here is that we have, what we think is a really potent and based on pre-clinically durable, way to silence KHK, that we can elaborate and we have a number of biomarkers that we can measure in the clinic that will help guide us along the path in terms of which of these indications to pursue, how to pursue them, et cetera. And this is also then a proprietary target within Alnylam that we're advancing. And so, we have really freedom to operate across a full range of diseases, and take it where the science and the unmet need drives us. So, look forward to sharing more data on that in the future.

[Leland Gershell, Oppenheimer]

Thank you.

[Yvonne Greenstreet, Chief Executive Officer]

Great. And yeah, thank you for highlighting, I think, another exciting opportunity in our pipeline and more to come towards the end of the year. Next question?

[Operator]

One moment for our next question. Our next question comes from Myles Minter of William Blair & Company. Your line is now open.

[Unidentified Analyst]

Hi. You've got Sarah on from Myles. Thanks for taking our question. Is there any clarity you can give on the timeline of advancing ALN-HTT into the clinic or any other assets that are using C16 conjugate technology, and how has this been informed by the clinical ALN-APP data thus far? Thank you.

[Yvonne Greenstreet, Chief Executive Officer]

The timelines for ALN-APP and any other programs using -- sorry.

[Unidentified Analyst]

HTT.

[Yvonne Greenstreet, Chief Executive Officer]

So HTT.

[Pushkal Garg]

Yeah. So, thanks Sarah for the question. I think, look, as I said in the remarks, and as you've heard from us in a couple of recent calls, I think what we've seen in the CNS space with ALN-APP has been really we think groundbreaking. It really opens up a whole new vista where we can take RNAi therapeutics to affect a wide variety of neuro-degenerative diseases and beyond in the CNF. When you look at what we see there, we see with the levels of up to 84%, 90% lower of lowering of soluble APP alpha and beta, that really signifies that we're getting deep brain penetration. That's always a big question as you're trying to think about additional targets that you can pursue, can you get into the deeper brain structures? And that level of knockdown signifies that.

And then you have durability where we're seeing knockdown pre-clinically that's now translating clinically and comper [ph] to what we saw in the liver. And we think these drugs can be dosed six months a year, or every six months or even less frequently. And so, that's exciting.

And then the third, and most critically frankly, is the fact that so far the solubility, this safety and tolerability is really encouraging as well. And so, this really opens up for us the opportunity to pursue multiple targets with our colleagues at Regeneron, who've been -- we've been working on in, in terms of this groundbreaking science.

And so, to your point, HTT is another molecule that we recently announced as a development candidate. We're doing preclinical work now, IND enabling work to bring that into the clinic. We haven't formally announced a timeline for that, but you can imagine that we're pursuing that rapidly. Our colleagues at Regeneron are advancing a molecule against for ALS, against SOD, also in preclinical development right now. And we have additional targets behind that that we're going to bring forward.

[Yvonne Greenstreet, Chief Executive Officer]

I think we have time for one last question.

[Operator]

One moment for our last question. Our last question comes from Mani Foroohar of Leerink. Your line is now open.

[Unidentified Analyst]

Hi. Good morning. This is Lily on for Mani. We had a question in terms of the commercial positioning for vutrisiran. What will be your strategy to protect the assets from the upcoming tafamidis genericization, and do you expect the need for a potential post-approval head-to-head study?

[Yvonne Greenstreet, Chief Executive Officer]

Tolga, I'm going to hand that question straight over to you.

[Tolga Tanguler, Chief Commercial Officer]

Yeah. I mean, first of all, thank you for that question. I guess, the question specifically for tafamidis, for cardiomyopathy indication, which we have yet to receive and obviously, how we're going to position the product is going to be dependent on HELIOS-B results. But one thing to really remind everyone, if you look at our polyneuropathy experience where the product is a different value in Europe and other markets, I wouldn’t say it has been a game changer and we've been able to accelerate growth and demand quite substantially in the markets that now AMVUTTRA is available versus tafamidis. And where we've seen an accelerated switch, particularly in Japan, where they have the polyneuropathy indication, unlike the US.

Like any company that wants to continue to drive patient value and patient growth, we will, of course, be looking into the post genericization and we will subsequently consider any alternative in terms of clinical trial and other options. But it's -- I would say it's a little too soon for us to consider that, and we will obviously keep you abreast of any important decision that we would make eventually.

[Operator]

I'm now showing no further questions at this time. I would like to turn the conference back to Alnylam for closing remarks.

[Yvonne Greenstreet, Chief Executive Officer]

Thank you and thanks everybody for joining us on this call. We're clearly very happy with a continued execution that we've seen in 2023 across multiple elements of our business, commercial, R&D and business development. And we look forward to sharing more progress in the coming months as we continue to deliver on our near and long-term goals. Thank you everybody, and have a great day.

[Operator]

This concludes today's conference call. Thank you for participating. You may now disconnect.